Epilepsy, a common neurological disorder characterized by recurrent spontaneous seizures, is considered to be a major health problem that affects approximately one to two percent of the population worldwide [Brown et. Al. N. Engl. J. Med., 2001, 344, 1145-1151.]. Epilepsy also poses a considerable economic burden on society. The direct costs of epilepsy vary significantly depending on the severity of the disease and the response to treatment. Despite the considerable progress in our understanding of the pathophysiology and pharmacotherapy of seizures and epilepsy [McNamara Nature, 1999, 399, A15-A22.], the cellular basis of human epilepsy remains an enigma. In the absence of etiological understanding, approaches to pharmacotherapy must be directed to the control of symptoms, that is the suppression of seizures. More concerning is that current antiepileptic drugs do not halt the underlying natural progression of the disorder.
Over the years, there has been considerable success in the development of novel antiepileptic drugs (AED) along with new improved formulations. These include older ‘first generation’ drugs such as carbamazepine, phenobarbital, valproic acid and newer, ‘second generation’ drugs such as lamotrigine, vigabatrin, tiagabine, topiramate, gabapentin and levetiracetam [Brazil C W, Pedly, T A, Ann. Rev. Med., 1998, 49, 135-162; McCabe P H. Expert Opinion. Pharmacother., 2000, 1, 633-674]. The selection of an antiepileptic drug for treatment is predicated on its efficacy for the specific type of seizures, tolerability and safety [Regesta G, Tanganelli P, Epilepsy Res., 1999, 34, 109-122; Kwan P, Brodie M J, N. Engl. J. Med., 2000, 342, 314-319].
Epileptic seizures can be either generalized (generalized epileptic seizure), originating in both hemispheres of the brain simultaneously, or partial (focal seizures) originating in one or more parts of one or both hemispheres, most commonly the temporal lobe. With generalized seizures, consciousness is always impaired or lost. Consciousness may be maintained in partial seizures but partial seizures may become generalized seizures in a process referred to as secondary generalization, at which point consciousness is lost. In patients the type of epilepsy or epileptic syndrome are further classified according to features such as the type of seizure, etiology, age of onset and electroencephalogram. Epilepsy or epileptic syndromes can be either idiopathic (etiology or cause is unknown) with a presumed genetic basis or symptomatic (acquired). The known potential causes of epilepsy include brain tumors, infections, traumatic head injuries, perinatal insults, developmental malformations, cerebrovascular diseases, febrile seizures and status epilepticus [Loscher W C, Trends Pharmacol. Sci, 2002, 23, 113-118].
Traditionally, pharmacological strategies for treatment of epilepsy are aimed at suppressing either the initiation or the propagation of seizures rather than the underlying processes that lead to epilepsy. Some epileptic patients are unresponsive to current antiepileptic drug treatment and for this reason the major goal in epilepsy research has been to develop drugs with greater anticonvulsant efficacy and less toxicity than existing drugs [Bauer J, Reuber M, Expert Opinion. Emerging Drugs, 2003, 8, 457-467]. There is growing evidence that lacosamide increases seizure threshold in a variety of experimentally-induced seizures (Bailer et al. Epilepsy Res. 2001, 43: 11-58; Bailer et al. Epilepsy Res. 2004, 61: 1-48; Duncan et al. Epilepsy Res. 2005, 467: 81-87, Lees et al. Neuropharmcology. 2006: 50:98-110). Lacosamide (R-2-acetamido-N-benzyl-3-methoxy-propanamide, SPM 927) is an anticonvulsant drug that belongs to a series of functionalized-amino acids (Kohn et al. J. Med. Chem. 1987, 30: 567-574). Lacosamide has shown activity in a wide variety of animal models of epilepsy including the maximal electric shock (MES) test, the rat hippocampal kindling and different models of self-sustaining status epilepticus ((Kohn et al. J. Med. Chem. 1996, 39: 1907-1916; Kohn et al. Bioorg. Med. Chem. 1999; 7: 2381-2389; Kohn et al. Bioorg. Med. Chem. 2001; 9: 293-2708; Malawska. Curr. Top. Med. Chem. 2005, 5: 69-85, Kohn et al. WO9733863, EP0888289, U.S. Pat. Nos. 5,773,475, 6,048,899, WO0000463).
A number of clinical anticonvulsants including phenyloin, carbamazepine, lamotrigine, gabapentin and pregabalin are widely utilized in the management of neuropathic pain [Collins et al. Expert Opinion Emerging Drugs, 2005, 10: 95-108]. Neuropathic pain results from a cascade of neurobiological events, which tend to induce electrical hyperexcitability in somatosensory conduction pathway. Since electrical hyperexcitability is also the hallmark of epileptic seizure activity, it is not surprising that anticonvulsants are among the first agents adopted in the treatment of neuropathic pain and remain the first option in clinical use. In addition to its anticonvulsive properties, Lacosamide has demonstrated antinociceptive activity in animal models of neuropathic pain and models of acute and chronic inflammatory pain [Stohr et al. Eur. J. Pain 2006, 10: 241-249; Selves et al. WO02074784; Stohr. WO 2005053667].
In recent years pain management has become an area of increasing focus in the medical profession, partly due to the growing elderly population, issues surrounding quality of life and the growing numbers of patients reportedly suffering from pain. Pain is both a sensory and emotional experience, and is generally associated with tissue damage or inflammation. Typically, pain is divided into two general categories—acute pain and chronic pain. Both differ in their etiology, pathophysiology, diagnosis, and most importantly treatment.
Acute pain is short term, and is typically of readily identifiable cause. Patients suffering from acute pain typically respond well to medications. In contrast, chronic pain—medically defined as pain that lasts for 3-6 months or longer, is often not associated with an obvious injury; indeed, patients can suffer from protracted pain that persists for months or years after the initial insult. Whilst acute pain is generally favorably treated with medications, chronic pain is often much more difficult to treat, generally requiring expert care.
According to the American Chronic Pain Association, over 86 million Americans suffer from chronic pain, and the management of chronic pain has long been recognized as an unmet clinical need. Most chronic pain is neuropathic in nature (also referred to as neuralgia). Neuropathic pain can, for instance, manifest itself as burning, stabbing, and shock-like sensations.
Unfortunately, neuropathic pain management is at best inconsistent, and often ineffective. This is in part due to the subjective nature of the pain, but also due to poor diagnosis, especially when the chronic pain is not clearly associated with a nerve injury or other insult. Moreover, few, if any, ethical drugs have been prospectively developed for the treatment of chronic pain. Instead, the current medications used to treat chronic pain are “borrowed” from other diseases, most commonly antiepileptic drugs and antidepressants.
Current first-line treatments for chronic pain include opioids, analgesics such as gabapentin, and tricyclic antidepressants. When opioids are administered over prolonged periods, undesirable side effects such as drug tolerance, chemical dependency and even physiological addiction can occur. Of treatment remedies currently available for chronic pain, at best approximately 30% are effective in significantly diminishing the pain, and even these may lose their efficiency over time. Although numerous pharmacological agents are available for the treatment of neuropathic pain, a definitive therapy has remained elusive.
In instances in which treatment with a single agent proves to be unsuccessful, combination therapy is often then explored as a second line treatment. For example, such combination therapy may employ administration of an opioid agent with an adjuvant analgesic, although the relative doses of each are often subject to prolonged trial and error periods. Often, triple drug therapy is necessary. Such therapy generally involves a combination of tricyclic antidepressants, anticonvulsants and a systemic local anesthetic. Patient compliance drops significantly, however, when treatment requires the administration of multiple pharmacologic agents. Recently, researchers reported the use of a combination of morphine and gabapentin in a randomized study for controlling nerve pain (Gilron, I., et al., N. Eng. J. Med., 352:1281-82, 2005).
It is not only important to consider overall pain relief, but also the type of pain relief. For example, chronic pain is typically viewed as allodynia or hyperalgesia. Allodynia is pain sensation from a stimulus which is not normally painful. This allodynia is typically caused by a physical stimulus and is thus referred to as tactile or mechanical allodynia. Hyperalgesia is an exaggerated sensation form a stimulus which is normally painful. The hyperalgesia can occur from a variety of stimuli but, commonly, a patient's reaction to hot or cold stimuli is reported. Importantly, physicians often report that the current drugs are most effective at relieving hyperalgesia, although most patients present allodynia, particularly mechanical allodynia.
In addition to poor and/or inconsistent efficacy, these medications have several other undesirable properties such as adverse events, duration of action, and complicated dosing and titration regimens.
The most common side-effect of the non-opiate drugs is sedation or somnolence. Based upon data from the package inserts for these drugs, as many as 20-30% of patients experience sedation. As mentioned above, the population greatest at risk for chronic pain is the elderly. For the elderly, experiencing significant and persistent sedation poses other risks, mainly locomotor function impairment. Such locomotors function impairment can lead to falls and the inability to perform many daily functions such as driving.
The duration of action is also a limitation for the most of the leading therapies. This is particularly important as pain, and especially nighttime pain, can lead to depression, insomnia and other factors which impact the patients' overall quality of life. A recent study suggests that patients with chronic pain and concurrent major depression and insomnia report the highest levels of pain-related impairment. This study also found that insomnia in the absence of major depression is also associated with increased pain and distress. (Wilson et al., Clin. J. Pain 2002, 18: 77-83.) Therefore, achieving pain relief with sufficient duration to achieve relief through the night is an important factor for neuropathic pain drugs. Pain-relief drugs such as gabapentin are taken once or more during the night to achieve pain relief, thus disturbing sleep and exacerbating the patient's overall quality of life.
Neuropathic pain (NP) is generally thought of a maladaptive chronic condition in which pain originates from damaged nerves, often yielding pain that is out of proportion to the extent of any injury. Damage can occur from a physical injury such as trauma or from chemical injury such as chemotherapeutics (e.g. paclitaxel). Neuropathic pain of this type is an important component of a number of syndromes of varying etiologies whose common characteristic is the development of a prolonged and profound pain state. Among these conditions are spinal cord injury, post-herpetic neuralgia, diabetic neuropathy, phantom limb pain, stump/neuroma pain, post-ischemic pain (stroke), fibromyalgia, complex regional pain syndrome (CRPS), chemotherapy-induced neuropathic pain, vertebral disk rapture, trigeminal neuralgia and others.
Recently, however, it has been recognized that neuropathic pain can also manifest itself in the absence of an identifiable nerve injury. These indications include AIDS and mirror image pain. The lack of any nerve injury but unmistakable chronic pain has led to increased interest in the role of glial cells in the maintenance of the neuropathic pain state (Watkins L R; Maier S F 2004, Drug Disc. Today: Ther. Strategies 1: 83-88; Watkins L R, Maier S F Nat Rev Drug Discovery 2003, 2:973-985). More specifically, recent research has demonstrated that glial cells enhance the release of neurotransmitters which relay pain information to the spinal cord and, even more strikingly, release substances which increase the excitability of pain-responsive neurons in the spinal cord. These substances, called pro-inflammatory cytokines, create and maintain exaggerated or pathological pain responses (Wieseler-Frank et al. Neurosignals 2005, 14: 166-174). Blocking the activation of glial cells reduces pro-inflammatory cytokines and reverses pathological pain. To date, no therapeutics have been approved which have a putative glial cell-attenuation mechanism for the treatment of neuropathic pain. Molecules which are glial cell-attenuators may play an important role in the treatment of neuropathic pain.
In light of the above shortcomings in current approaches for treating chronic pain there exists a need for improved compositions and methods for treating pain, particularly neuropathic pain and its associated symptoms and, more specifically, neuropathic pain associated with certain conditions such as fibromyalgia, among others. Such approaches should ideally overcome one or more of the problems associated with existing methods for treating chronic pain. The present invention meets these needs.
At present no analgesic exists which is highly potent in various pain syndromes. Different mechanisms leading to inflammatory or neuropathic pain make it difficult to identify compounds which have general analgesic activity. We are only at the beginning of understanding the mechanisms behind different pain syndromes like cancer pain (e.g. tumor-induced bone cancer pain), chemotherapy-induced pain or nucleoside-induced pain, all of which seem to have various molecular origins. Antidepressants, anticonvulsants or opioids, which describe groups of compounds used in pain treatment, do not have a common pattern regarding their efficacy in treatment of pain syndromes. This makes it difficult to predict the activity of new compounds in the various pain syndromes and demands a detailed characterization in multiple models of pain in animals.
Neuropathic pain after injury or dysfunction to the peripheral or central nervous system remains a difficult clinical problem for which effective treatments are lacking (Bennett, 1994, Ann. Neurol. 35: S38-S41; Murphy and Reid, 2001 Ref.?). Anticonvulsants are used for the management of some forms or neuropathic pain (Sindrup S H; Jenssen T S, Pain 1999, 389-400; Jensen, 2002, Eur. J. Pain 6: 61-68).
Bone is the third most common site of metastasis after lung and liver, and is the primary site of metastatic disease in patients with breast, prostate and lung cancer. The bone lesions that result from metastatic disease also cause severe bone pain, which is a major clinical problem in cancer patients. This type of pain is difficult to treat due to its intermittent, progressive nature and its aggravation by movement. The predominant symptom in this model of pain is mechanical allodynia. Thermal hyperalgesia and mechanical hyperalgesia have also been demonstrated as measured by the weight bearing difference in the two hind limbs (Medhurst et al., 2002, Pain 96: 129-140). Treatment of bone pain in human patients is largely limited to the use of opioids. However, the efficacy of potent opioids is minimal, and effective doses produce a range of debilitating side effects. Consequently, there is a clinical need for new therapies which can be used to prevent, treat and alleviate tumor-induced bone pain. Candidate therapies for treatment of tumor-induced bone pain can be evaluated using a rat model, as the rat is superior for testing behavioral responses to pain stimuli. One such model involves the injection of rat mammary gland carcinoma cells into the marrow space of the proximal tibia, using an endpoint of pain assessment (Medhurst et al., 2002, Pain 96: 129-140), which was performed on days 7 to 15 following tumor implantation.
Chemotherapy-induced pain is a form of neuropathic pain associated with neurotoxic drugs such as vinca alkaloids (e.g. vincristine) and is characterized by painful paresthesias and dysesthesias. The clinical antineoplastic efficacy of vincristine is limited by the development of a mixed sensorimotor neuropathy (Casey et al., Brain. 1973, 96: 69-86; Tanner et al., J Neurosci. 1998, 18: 6480-6491) which appears to occur in two major stages (Weiss et al., N Engl J. Med. 1974, 291:127-133). In the early stage, peripheral axons are damaged by vincristine and the principal symptoms are paresthesias and dysesthesias. In the later stage, which occurs more frequently when higher doses are given for longer periods of time, axons are lost and the principal clinical finding is loss of motor function. The described vincristine rat model seems to reflect the early stage of vincristine-induced chemotherapeutic neuropathy. Whilst the underlying mechanism is not fully understood as yet, it has been described as causing a disorganization of the axonal microtubule cytoskeleton, as well as an increase in the caliber of unmyelinated sensory axons (Quasthoff S, Hartung H P J. Neurol. 2002, 249: 9-17). These results demonstrate that changes in microtubule structure in nociceptive sensory neurons accompany vincristine-induced hyperalgesia.
Painful peripheral neuropathy induced by nucleoside analogues is becoming recognized and an important source of morbidity in human immunodeficiency virus (HIV) infected individuals (Cohen, 2002). This severely debilitating side-effect may force abbreviation or even discontinuation of AIDS (acquired immunodeficiency syndrome) therapy (Yatvin et al., 1999). This neuropathy is characterized by a sudden onset of intense burning discomfort in both feet sparing the hands at about the 10th week of treatment, and which reaches severe intensity over a period of days (Dubinsky et al., 1989). The biochemical mechanism underlying this side-effect remains to be clearly established, although mitochondrial toxicity has been reported to contribute to its development. Recently, it has been reported that treatment of rats with antiretroviral nucleoside analogue AIDS therapy drugs ddC (2′,3′-dideoxycytidine), ddI (2′,3′-dideoxyinsine) or d4T (2′,3′-didehydro-3′-deoxythymidine) produces enhanced nociception in the rat (Joseph et al., 2004). The mechanism involved appears different from that of other models of metabolic or toxic painful peripheral neuropathy, as anti-hyperalgesic drugs are effective in these models. Inhibitors of protein kinase A, protein kinase C, protein kinase G, p42/p44-mitogen-activated protein kinase (ERK1/2) and nitric oxide synthase have no effect on peripheral neuropathies, and had no effect on nucleoside reverse transcriptase inhibitor-induced hypersensitivity. Intracellular calcium modulators (TMB-8 and Quin-2) are the only agents capable of reversing this hypersensitivity of intoxicated animals strongly suggests the role of intracellular calcium in this type of neuropathic pain.
Chemotherapy, e.g. treatment with vinca alkaloids like vincristine or with taxol, suramin, cisplatin, carboplatin or oxaliplatin is used for the treatment of cancer and HIV patients. Additionally, HIV or/and tumor patients are also treated with antiretrovirals or antivirals. Recently, Lacosamide has been shown to be potentially useful for treating tumor pain, in particular bone cancer pain, for treating chemotherapy-induced pain and for treating nucleoside-induced pain.
The pathophysiology of migraine is thought to involve activation of trigeminal afferents [Goadsby et al N. Eng. J. Med. 2002, 346: 95-108] The trigeminal sensory nerve fibers that innervate cranial structures contain the neuropeptide calcitonin gene-related peptide (CGRP). Activation of Aδ-trigeminal nerve fibres causes the release of CGRP and dilation of dural arteries in animals, whilst CGRP levels in the blood plasma of migraineurs are increased during a migraine episode. Intravenous injection of CGRP causes a dull headache and subsequent migraine in humans and dural blood vessel dilation in rats. Recent clinical evidence suggests that blockade of CGRP has a potent acute antimigraine effect [Olesen et al. N. Eng. J. Med. 2004, 350: 1104-1110].
Interestingly, there is also strong evidence that Cortical Spreading Depression (CSD) serves as an initiating event for migraine visual aura and pain [Moskowitz et al. Nat. Med. 2002, 8:136-142]. CSD is a transient suppression of cortical activity, which starts locally and spreads throughout the tissue. CSD usually leads to trigeminal activation and, putatively, to the release of CGRP. Lacosamide has been shown to suppress CSD and to reduce CSD-induced release of CGRP and is therefore of potential importance in the clinical treatment of acute migraine, the prophylactic treatment of migraine and for the treatment of other forms of chronic headache and/or CSD-associated disorder [Stohr et al. WO 2005099740]
More recently lacosamide has demonstrated efficacy in the reserpine-induced vacuous chewing movement, a mouse model of tardive dyskinesia, suggesting the potential clinical utility of this compound in the prevention, alleviation and/or treatment of dyskinesia [Stohr et al. WO 2005110390]. Dyskinesia is a common complication of L-DOPA pharmacotherapy in Parkinson's disease, and is thought to depend on abnormal cell signaling in the basal ganglia [Cenci et al. Exp. Neurol. 2005, 194: 66-75].
Although lacosamide displays potential utility in a wide variety of CNS disorders the methoxy group undergoes significant demethylation to the O-desmethyl metabolite. As a result, any attempt to block this demethylation pathway could improve the overall clinical profile.
It has now been found that a novel class of fluorinated serine derivatives is useful in the treatment of epilepsy, neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia and other related CNS disorders.